Osteoporosis is a disease in which bones pathologically are aged and become brittle. In general, the pathological conditions of osteoporosis, per se, are often non-symptomatic or with slight symptoms. However, if bone fracture is once caused, the disease may present severe symptoms depending on the position or degree of the fracture. Predilection sites of bone fractures are metaphyseal regions of appendicular skeletons and spines, and in particular, femoral neck fracture, compressed fracture of spine vertebra, fracture of distal end of radius, and fracture of proximal end of humerus are regarded as four major fractures in osteoporosis. It is generally difficult to reduce a fracture with osteoporosis by a therapeutic treatment because of the brittle property of the bone, and a problem arises that sufficient fixation can be hardly obtained even by osteosynthesis. Disuse of the whole body will readily advance with fractures, and various and severe complications such as muscular weakness, joint contracture, decubitus, dementia, urinary tract infection, and cardiopulmonary dysfunction are easily caused. Moreover, a vicious circle will likely occur in which disuse bone atrophy simultaneously advances, and as a result, osteoporosis is further aggravated.
As described above, fractures with osteoporosis degrade the quality of life (QOL) of patients, greatly affect the vital prognosis, and in addition, cause extremely serious social problems such as increases of caring burden and medical expense. Therefore, targets of therapeutic treatments of osteoporosis are to quickly promote osteogenesis to increase bone mass and thereby prevent bone fractures, and for patients suffered from existing fractures, to quickly increase bone mass in a similar manner to promote early leave from sickbeds and release the patients from risks of complications resulting from the bedridden status.
The pathological condition of bone fracture, per se, is an impairment which may occur all over generations due to various causes other than osteoporosis, and healing therefrom requires rather long period of time, if not with osteoporosis. For this reason, fractures significantly disturb activities of daily living (ADL) of patients, and clinical cases may sometimes occur in which normal recovery is not observed such as incomplete synostosis, protracted healing, and malunion. Therefore, for bone fractures, targets of the therapeutic treatments are also to quickly promote osteogenesis after injury to promptly increase bone mass and thereby shorten a period required for fixation of fractured site or period in bedridden status.
As prophylactic and/or therapeutic agents for skeletal diseases including osteoporosis and bone fracture, calcium preparations, estrogen preparations, selective estrogen receptor modulators (SERM), active vitamin D3 preparations, vitamin K preparations, ipriflavone preparations, calcitonin preparations, bisphosphonate preparations, parathyroid hormone preparations, anabolic hormone preparations, bone morphogenic proteins (BMP), fibroblast growth factors (FGF) and the like have been clinically used so far, or clinical applications thereof have been studied so far. However, despite the use of the variety of drugs, the number of patients of skeletal diseases has been increasing year by year. For example, the number of patients of femoral neck fracture is estimated to be 1,700,000 all over the world as of 1990, and the number is predicted to increase up to 6,300,000 in 2050. Therefore, the prophylactic and/or therapeutic effects of the conventional medicaments for the skeletal diseases are not fully satisfactory effects, and developments of innovative medicaments that exhibit higher effects than those of the conventional medicaments have been desired.
Prostaglandin E2 (hereinafter abbreviated as “PGE2”) is known to have various physiological functions such as algesic action and oxytocic action, and regulatory action on bone metabolism is also reported. It is really reported that when PGE2 is given to experimental animals such as rats or humans, osteogenesis rises and bone mass increases. It is also reported that when PGE2 is topically administered to a bone in the form of a sustained release drug, osteogenesis of the site is promoted. Further, it is reported that when PGE2 is added to a marrow cell culture system, the calcified bone-like node formation and the alkaline phosphatase activity as the marker of differentiation of osteoblasts increase, and therefore an efficacy of positively promoting osteogenesis can be expected for PGE2. For this reason, in contrast to the conventional medicaments, which hardly achieve recovery from skeletal diseases although they delay the advance, PGE2 may possibly be a medicament having extremely high usefulness.
However, since PGE2 exhibits the side effects which should be avoided for continuous administration for a long period of time, such as the algesic action and oxytocic action as described above, researches have been extensively conducted aiming at obtaining PGE2 derivatives which selectively act on bones. Four kinds of different receptor subtypes (EP1, EP2, EP3, EP4) are reported so far in human as receptors of PGE2, and expression sites and intracellular signal transduction systems for the activation of these subtypes are different. Accordingly, for example, one attempt is to newly provide bone-selective PGE2 derivatives by creating a subtype-specific agonist for each subtype.
At least two kinds of receptors, EP2 and EP4, have been reported as the receptors of PGE2 expressed in osteoblasts, and in particular, EP4 is reported to be deeply involved in the osteogenesis function, because an antagonist thereof suppresses the formation of the calcified bone-lime nodes in a marrow cell culture system (M. WEINEB, A. et al., Am. J. Physiol., 276, E376-E383, 1999). Therefore, EP4 agonists are promising as skeletal disease curing agents. EP2 also has a function of increasing cAMP in osteoblasts through conjugation with the Gs protein like EP4. Accordingly, EP2 agonists are also expected to be therapeutic agents for skeletal disease. Actual clinical applications of EP2 agonists and EP4 agonists as therapeutic agents for skeletal disease have been attempted. However, they are not clinically convenient because, for example, the route of administration thereof are limited to sustained release local administration, intravenous drip infusion and the like.
As heterocyclic compounds having similar action to that of the compounds of the present invention, compounds described in the following patent documents: International Patent Publications WO02/24647, WO02/42268, WO03/007941, WO03/035064, WO04/63158, WO04/85430, and U.S. Pat. No. 6,747,037 are known. However, structural features of any of these compounds are different from those of the compounds of the present invention.